Rewiring of de novo serine synthesis supports tumorigenesis under deficiency of TET2

  • Br J Cancer. 2026 Jun 26. doi: 10.1038/s41416-026-03526-7.
Ke Zheng  #  1 ,  Keqiang Rao  #  2 ,  Xiaoxu Lu  1 ,  Miaomiao Yang  1 ,  Hui Wu  3 ,  Zhilong Ai  4 ,  Jing He  5
Affiliations
  • 1. Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
  • 2. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3. Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. [email protected].
  • 4. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 5. Optogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42362869 DOI: 10.1038/s41416-026-03526-7
Abstract

Background: Ten-eleven translocation 2 (TET2) is initially identified as a mammalian DNA dioxygenase to orchestrate expression of numerous genes and diverse interplays of physiological and pathological processes. Beyond its canonical role, the moonlight functions of TET2 have been gradually uncovered.

Methods: RNA-seq, qPCR and western blot are employed to validate expression of genes. ChIP and RIP analyses are conducted to test the enrichment of genes. Stable isotope labelled glucose is utilized to analyze the metabolic flux. Xenograft analysis is performed to explore growth of tumour in vivo.

Results: TET2 binds to and oxidizes mRNA 5-methylcytosine (m5C) of the transcription factors ATF3 and ATF4, thereby enhancing mRNAs degradation. Deficiency of TET2 rewires de novo serine synthesis and the viability of hepatocellular carcinoma (HCC) cells. Both ATF3 and ATF4 are required to sustain transcription of de novo serine synthesis Enzymes and the associated metabolic reprogramming under TET2 loss. Ultimately, ATF3 collaborates with ATF4 to contribute to growth of tumours lack of TET2. Deficiency of TET2 sensitizes HCC tumours to serine restriction.

Conclusions: Our findings not only elucidate a heretofore unrecognized mechanism of transcriptional suppression of de novo serine synthesis Enzymes, but also propose a targetable vulnerability of HCC tumours.

Products